Dopaminergic neuron degeneration leads to Parkinson's disease, which is highly prevalent in older adults. As the second most common neurodegenerative disease and the most common movement disorder, Parkinson's disease is characterized by the loss of ventral midbrain substantia nigra dopaminergic neurons that control movement, mood, and motivation. Most cases of Parkinson's disease are age-dependent and sporadic, with about 5% are familial. Oxidative stress, including that induced by environmental toxicant 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and herbicide Paraquat, has been demonstrated to contribute to dopaminergic neuron degeneration in sporadic Parkinson's disease. But the molecular mechanism underlying oxidative stress-induced dopaminergic neuron degeneration remains largely unknown. This proposal aims to use MPTP-treated mice as an oxidative stress-induced Parkinson's disease model, together with knockout mice and cultured dopaminergic neurons to elucidate how oxidative stress can induce dopaminergic neuron degeneration. Specifically, this proposal will focus on SIRT1, a NAD-dependent protein deacetylase that is a master regulator of stress response, and forkhead transcription factor FOXA2, which was recently shown to be specifically expressed in mouse ventral midbrain dopaminergic neurons regulating their survival and development. This proposal plans to characterize the deacetylation of FOXA2 by SIRT1 in response to oxidative stress in dopaminergic neurons, and to address questions including what sites does SIRT1 deacetylate FOXA2 in vivo, how do these deacetylation events affect FOXA2 activity, and whether SIRT1 is involved in regulating dopaminergic neuron degeneration in response to oxidative stress in vivo. Together, these studies will test the novel roles of SIRT1 and SIRT1-mediated deacetylation of FOXA2 in Parkinson's disease pathogenesis. Findings from the proposed research will also provide new insights into the molecular mechanism underlying oxidative stress-induced dopaminergic neuron degeneration, which will hopefully lead to new strategies to better diagnose and treat Parkinson's disease and other neurodegenerative disorders.